2,2,2-Trifluoroethanol → 3-Methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid

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Reaction Steps

Sodium, which had been stored in mineral oil, was rinsed in hexane and cut into approximately 70-mg slivers. Those slivers of sodium (0.37 g, 16.08 mmol) were loaded into a 150-mL resealable vessel. The vessel was purged with argon, placed in a water bath, and 2,2,2-trifluoroethanol (31.2 mL, 429 mmol) was added. Bubbling ensued immediately. Bubbling had ceased and sodium had disappeared around 30 minutes. The mixture was stirred at room temperature for another 30 minutes. To this mixture was added methyl 5-chloro-3-methylpyrazine-2-carboxylate (1.00 g, 5.36 mmol). The vial was sealed and heated at 45° C. overnight. After addition of 1 M sodium hydroxide (5.90 mL, 5.90 mmol), the mixture was stirred at 45° C. overnight. The reaction mixture was concentrated to remove most of the trifluoroethanol. The residue was dissolved in the minimum amount of water (300 mL), and the aqueous phase was washed with diethyl ether (2×30 mL). The aqueous phase was acidified with 5 M HCl (5 mL). The aqueous phase was extracted with DCM until TLC (15% MeOH-DCM) showed product wasn't coming out any more. The organics were combined, dried over MgSO4 and concentrated to give 3-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (1.28 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ ppm 10.57 (br, 1H), 8.15 (s, 1H), 4.87 (qt, 2H, J=8.2), 2.93 (s, 3H).

Provenance & Evidence